Androgen Replacement

Hans SS, Dhindsa SS, Chemitiganti R. Testosterone replacement and cardiovascular safety: no straight and narrow! Clin Med Insights Cardiol. 2015;9:33-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412415/

The past decade has seen a tremendous increase in the number of men treated for hypogonadism with the expectation of symptomatic benefit. However, the long-term cardiovascular safety of testosterone replacement remains unknown because retrospective studies of testosterone replacement have been inconsistent, and definitive, prospective, randomized studies are lacking. The purpose of this review is to critically appraise the studies on testosterone replacement and cardiovascular outcomes.
 
Low free testosterone is associated with hypogonadal symptoms in men with normal total testosterone levels: results from the European Male Ageing Study
http://www.endocrine-abstracts.org/ea/0037/ea0037OC2.4.htm

Background: During ageing, total testosterone (TT) declines and SHBG increases, resulting in a greater decline of free testosterone (FT) compared to TT. However, guidelines suggest using TT to diagnose androgen deficiency and to reserve FT only for men with borderline TT. We investigated if isolated low FT or isolated low TT was associated with androgen-related endpoints in healthy men.

Methods: 3369 community-dwelling men, aged 40–79, were included. We assessed differences between men with both normal TT (≧10.5 nmol/l) and calculated FT (≧220 pmol/l) (referent), men with normal TT/low FT (group 1) and men with low TT/normal FT (group 2) by descriptive statistics and ordinal logistic regression adjusted for age, centre, BMI and comorbidities.

Results: 2540 men had normal TT (18.4±5.5 (mean±S.D.) nmol/l) and FT (326±75 pmol/l). There were 261 men in group 1 (normal TT (14.2±3.7 nmol/l), low FT (195±22 pmol/l)) and 92 men in group 2 (low TT (9.6±0.7 nmol/l), normal FT (247±20 pmol/l)).

Compared to referent, men in group 1 were older and had higher SHBG, whereas group 2 was younger and had lower SHBG. BMI was higher in both groups. Men in group 1, but not group 2, were in poorer health and had lower haemoglobin. Regression analysis showed that men in group 1 had less frequent morning erections (P=0.012), more erectile dysfunction (P<0.001) and more physical symptoms (limited vigorous activity (P=0.011), walking 1 km (P=0.026) and bending (P=0.005)). Compared to referent, sexual and physical symptoms did not differ in group 2.

Conclusions: Independent of age, BMI and comorbidities, men with isolated low FT, but normal TT, have more androgen deficiency-related symptoms than men with normal TT and FT levels; whereas symptoms do not differ in men with isolated low TT. Not only total, but also FT levels should therefore be assessed in men with hypogonadal symptoms.
 
Ironic you post this study after you totally berated a poster for considering trt based on low free T, high shbg and normal total testosterone. Clearly there are plenty of doctors and others out there who thoroughly disagree with you on this issue, and again the fact that you hurl insults at someone seeking help w these kind of numbers w hypo gonadal symptoms is telling. Perhaps a dose of humility is in order, or at least an ounce of open mindedness.
 
Jenkins LC, Mulhall JP. Editor's Comment - How Dangerous is Testosterone Supplementation? Int Braz J Urol. 2015;41(2):195-8. http://www.brazjurol.com.br/march_april_2015/Editors_Comment_195_198.htm

Recently, significant media attention has been focused on testosterone supplementation therapy (TST) and increased cardiovascular (CV) risk. Treatment for testosterone deficiency syndrome (TDS) has been on the rise in the past several years. US Food & Drug Administration (FDA) drug utilization data showed sales increased 65% between 2009 and 2013.

The true prevalence of TDS varies based on the source, definition of the condition and age of population studied, however, it is believed to range from 2-39%.

Patients suffering from TDS are at an irrefutably increased risk for bone density loss, development of type 2 diabetes (T2DM), anemia, sarcopenia, cognitive deficits, and premature death. Shores et al, have shown increased mortality rates in men with low testosterone (mortality rates with normal, equivocal, and low testosterone levels were 20%, 25%, 35% respectively).

Patients should be made aware of possible adverse events associated with TST in particular as polycythemia and hyperestrogenism.

Polycythemia is believed to be a dose-dependent effect and hematocrit levels should be maintained below 54% to prevent hyperviscosity-related events.

Hyperestrogenism is a response of testosterone conversion to estrogen via aromatase in adipose tissue and may be associated with gynecomastia.

Two recent meta-analyses have shown that prostate related events (rates of prostate cancer, PSA >4 ng/mL, prostate biopsies) were not statistically significantly higher in the testosterone supplementation group compared to the placebo group. Also these meta-analyses demonstrated no significant elevation in CV risk.

In a meta-analysis by Aruajo et al., the authors reported that testosterone levels ≥2.18 standard deviations below normal range were associated with 35% and 25% elevated risk in all-cause mortality and CV disease mortality, respectively. However, the authors note that their analysis showed considerable between-study heterogeneity limiting the clinical extrapolation of the data.

Some of the difficulty addressing research in TST relates to the methodological challenges related to studying patients with TDS, including: population heterogeneity, circadian rhythm of testosterone secretion, use of total vs. free testosterone, number of pre-treatment testosterone levels, covariate analysis, duration and follow-up of TST. There is often significant heterogeneity in the populations being studied therefore limiting the validity of comparative analyses.



Overall, these three papers claiming increased CV risks in patient using TST are all inherently flawed and limit the interpretation of the data and the clinical applicability is questionable.

Especially when more than two decades of good science and the Araujo meta-analysis have found quite the opposite, that TDS is associated with a higher incidence of CV events. Finally, more recently, Corona et al show in a large meta-analysis no association between TST and increased CV risk.

In September 2014, a US Food and Drug Administration advisory panel met and determined more studies are needed to identify the true CV risk with TST and they recommended changing labeling to stress use only in those patients with a diagnosis of hypogonadism. In December 2014, the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee determined there was no consistent evidence of an increased CV risk with the use of TST.

With this, the media attention surrounding TST has declined and most importantly, our clinical practice regarding TST prescribing and what we tell patients has not changed.
 
Pongkan W, Chattipakorn SC, Chattipakorn N. Roles of Testosterone Replacement in Cardiac Ischemia-Reperfusion Injury. J Cardiovasc Pharmacol Ther. http://cpt.sagepub.com/content/early/2015/05/25/1074248415587977.abstract

Testosterone is an anabolic steroid hormone, which is the major circulating androgen hormone in males. Testosterone levels decreasing below the normal physiological levels lead to a status known as androgen deficiency. Androgen deficiency has been shown to be a major risk factor in the development of several disorders, including obesity, metabolic syndrome, and ischemic heart disease.

In the past decades, although several studies from animal models as well as clinical studies demonstrated that testosterone exerted cardioprotection, particularly during ischemia-reperfusion (I/R) injury, other preclinical and clinical studies have shown an inverse relationship between testosterone levels and cardioprotective effects.

As a result, the effects of testosterone replacement on the heart remain controversial. In this review, reports regarding the roles of testosterone replacement in the heart following I/R injury are comprehensively summarized and discussed.

At present, it may be concluded that chronic testosterone replacement at a physiological dose demonstrated cardioprotective effects, whereas acute testosterone replacement can cause adverse effects in the I/R heart.
 
Defending Testosterone, Debunking the Myths
http://www.medscape.com/viewarticle/845705

The effects of testosterone deficiency (also called "hypogonadism" or, informally, "low T") have been recognized for millennia. The treatment of hypogonadism has been described in medical textbooks for decades, and the symptoms are observed daily in medical practices across the country.

Still, the use of supplemental testosterone has always been controversial, perhaps more so today than ever before. Its ability to improve men's sexual symptoms, boost energy, and enhance well-being were quickly recognized after it was first synthesized in 1935.

By 1941, however, it was reported that testosterone "activated" prostate cancer, inciting a fear among physicians that has persisted for more than 70 years.

Shockingly, the decades-old belief that testosterone therapy would precipitate rapid prostate cancer growth was based on uninterpretable results in a single patient! Yet this fear established a dominant narrative that was impervious to substantial evidence to the contrary.


The latest concern about testosterone is over potential cardiovascular (CV) risks. In March, the US Food and Drug Administration (FDA) issued a warning about testosterone's possible CV risks, and advised that testosterone therapy not be initiated for "age-related" symptoms.

The controversy is eerily similar to the one involving prostate cancer so many years ago—a rush to judgment based on the weakest of evidence. As the inimitable Yogi Berra might say, "It's like déjà vu all over again."
 
Sell A Disease To Sell A Drug
http://www.washingtonpost.com/opinions/the-bulked-up-campaign-around-low-testosterone/2015/06/07/a9abda16-0573-11e5-8bda-c7b4e9a8f7ac_story.html

Seven years, at least 25 million prescriptions and $9.7 billion in sales too late, the Food and Drug Administration is finally pushing back against the over-prescribing of testosterone.

Last month, in response to new FDA rules, testosterone manufacturers released new instructions for doctors making it clear that testosterone is not approved for “low-T” — a marketing term developed by drug companies to describe men with low testosterone levels caused by aging. Companies must now warn doctors about a possible increased risk of heart attack and stroke in men who take these drugs.

The FDA rules came about after the agency announced in March that it “has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging. The benefits and safety of this use have not been established.”

Why are so many men taking testosterone for an unapproved use? The nearly tenfold increase in testosterone prescriptions began in 2007 when Abbott Laboratories (now AbbVie) launched its award-winning “Is It Low-T?” disease awareness campaign. The campaign has urged countless middle-age men who would like to become thinner, more muscular, more energetic and more sexually satisfied to ask their doctors whether low testosterone could be the reason they have gained weight, sometimes feel sad or grumpy, or get sleepy after meals.

A quiz on the http://www.isitlowt.com/ (“Is It Low-T?” Web site) — which, perhaps in a positive sign, was taken down for unspecified “upgrades” last month — told men if they should have their testosterone level checked. (A company spokeswoman said last week that she could not answer our questions about the status of the site.) One of us — feeling grumpy, low energy and a little sleepy after dinner — took the quiz in the days before the site was removed and was told to talk his doctor about having a blood test. The Web site even instructed visitors in how to ask. Suggested questions included, “Considering my symptoms, should I be tested for Low T?” — helpful if your doctor is a little slow or happens to read the New England Journal of Medicine, which in 2010 published a studydebunking the value of symptoms besides those related to sexual activity, like those covered by seven of the 10 quiz questions, in making a diagnosis (the question on loss of height was not tested).

Company-funded disease awareness campaigns often blur the line between public health messages that increase awareness about important diseases and infomercials meant to sell a disease to sell a drug. It’s a simple formula: The more diagnoses doctors make, the more prescriptions they can write. The “Is It Low-T?” campaign appears to be about getting as many men as possible diagnosed.

The problem is that it’s not about getting the right men (and boys) diagnosed, such as those who have low testosterone because of trauma, chemotherapy, genetic abnormalities, undescended testes or some other serious underlying problem. These patients need testosterone to develop normally or to restore “malenesss” and sexual function. They don’t need an awareness campaign, because treating them is standard medical practice.

As the FDA now acknowledges, the benefits and harms of treating men for “low-T” related to aging are unknown. For many men, the symptoms highlighted in the ads may not even be related to their level of testosterone. That’s why the FDA’s endocrine advisory committee questioned whether “low-T” of aging is even a disease at all. Or whether, in the words of comedian Stephen Colbert, “low-T” is simply “a pharmaceutical company-recognized condition affecting millions of men with low testosterone, previously known as getting older.”

According to the FDA, the dramatic rise in testosterone use is overwhelmingly in men with “low-T” of aging. If testosterone is not approved for these men — the target of “Is It Low-T?” — then why didn’t the FDA stop the campaign years ago?

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM416461.pdf that it has received complaints about the campaign but told the endocrine advisory committee it could not act. The agency maintains that it can only regulate a disease awareness campaign if the campaign mentions a specific drug by name. But it can regulate campaigns when an unnamed drug is uniquely identified, as is the case with “low-T.” Here, the treatment is testosterone. The campaign has specifically mentioned “testosterone” in all its available forms (tablet, patch, roll-on, gel, etc.) as the recommended treatment.

And even if the FDA were powerless, it could still refer the matter to the Federal Trade Commission. It’s not clear how often the FDA makes such referrals, and the Federal Trade Commission declined to comment when asked whether the FDA had referred the low-T campaign. But the bottom line is: Neither the FDA nor the Federal Trade Commission has taken public action to limit or eliminate the “low-T” campaign. For years, consumers have been subjected to so-called disease awareness advertising and marketing that clearly crossed the line into off-label drug promotion.


Unfortunately, “Is It Low-T?” is not unique. It’s just a particularly bulked-up example of what has become standard operating procedure for drug companies. Regulators must be vigilant about such campaigns and act right away when they cross the line. They must not let manufacturers exploit what is essentially a regulatory blind spot.

The FDA’s recent action changing the official prescribing information for doctors may help reduce inappropriate prescriptions for “low T” related to aging — and that’s a good thing. But it’s not enough. The agency needs to flex its regulatory muscle and eliminate any so-called “disease-awareness” campaigns that promote drugs for off-label uses. Otherwise, how much of a dent can the FDA’s action really make when millions of men have been told that aging is optional?
 
Maganty A, Osterberg EC, Ramasamy R. Hypogonadism and Testosterone Therapy: Associations With Cardiovascular Risk. American Journal of Men's Health. 2015;9(4):340-4. http://jmh.sagepub.com/content/9/4/340.abstract

Testosterone replacement therapy (TRT) use is increasing, primarily in men with symptomatic hypogonadism. There are many benefits associated with TRT use, including improved sexual function, improved bone mineral density, and increased free fat mass and strength. As TRT use increases, its role on cardiovascular health must be explored.

While previous evidence identified no adverse cardiovascular risks associated with TRT use, more recent studies suggest that there may be an associated risk, especially in elderly men and younger men with cardiac disease. Care must be taken with TRT use in these groups of men by careful monitoring for cardiac dysfunction.

While testosterone therapy has many benefits and may generally be well tolerated, those prescribing the therapy must be cognizant of the potential adverse cardiovascular risks and advise men on the potential risks versus benefits.
 
Canup R, Bogenberger K, Attipoe S, Jones DR, Olsen CH, et al. Trends in Androgen Prescriptions From Military Treatment Facilities: 2007 to 2011. Mil Med. 2015;180(7):728-31. http://publications.amsus.org/doi/abs/10.7205/MILMED-D-14-00496

INTRODUCTION: The role of testosterone in health and quality of life has become increasingly visible and overtly marketed to the public. Some evidence suggests that testosterone levels in men may be low because of a variety of reasons, including stress and environmental exposures.

OBJECTIVE: This study examines trends in testosterone prescriptions dispensed by military treatment facilities (MTFs).

METHODS: We examined data from the Department of Defense Pharmacy Data Transaction Service to determine the nature of androgen prescriptions dispensed through MTFs from 2007 through 2011.

RESULTS: The number of androgen prescriptions increased more than two-fold across the military from 19,494 in 2007 to 45,270 in 2011. Most prescriptions (99%) were for men. Androgen prescription rates rose 23% per year from 2007 through 2011 (p < 0.001, CI 23-24%). The prescription rate for 35- to 44-year-olds increased more than any other age group, with annual increases averaging 33% (p < 0.001, CI 32-34%).

CONCLUSION: The number of androgen prescriptions within MTFs rose significantly from 2007 through 2011. This is similar to rises in androgen prescriptions seen in civilian medical systems. Clinical indications for the sharp increase in testosterone prescriptions are unknown, and the indications for clinically appropriate testosterone replacement need further clarification.
 
Tan RS, Cook KR, Reilly WG. Myocardial Infarction and Stroke Risk in Young Healthy Men Treated with Injectable Testosterone. Int J Endocrinol. http://www.hindawi.com/journals/ije/2015/970750/

This study was conducted to examine the association between testosterone therapy and new myocardial infarction (MI) and stroke events in a series of patients treated at Low T Centers across the United States, consisting of mainly young (mean age = 46), otherwise, healthy men.

Electronic medical records were queried between the years 2009 and 2014 to identify patients diagnosed with hypogonadism, MI, and stroke, as indicated by ICD-9 codes. The incidence of MI and stroke events was compared to community-based registries.

39,936 patients recruited from 40 Low T Centers across the United States were treated and 19,968 met eligibility criteria for receiving testosterone treatment.

The incidence rate ratio (IRR) for MI in testosterone- (T-) treated versus nontreated patients was 0.14 (C.I. = 0.08 to 0.18, P < 0.0001) whereas the IRR for stroke for T-treated versus nontreated patients was 0.11 (C.I. = 0.02 to 0.13, P < 0.0001).

There was no evidence of worsening preexisting MI or stroke in patients treated with testosterone.

The experience in Low T Centers shows that, in an injectable testosterone patient registry, testosterone is generally safe for younger men who do not have significant risk factors.

Of patients that developed MI with testosterone, there was no association with testosterone or hematocrit levels.
 
Ungureanu MC, Costache, II, Preda C, Mogos V, Vulpoi C, et al. Myths and Controversies in Hypogonadism Treatment of Aging Males. Rev Med Chir Soc Med Nat Iasi. 2015;119(2):325-33. http://www.revmedchir.ro/uploads/1/5/7/2/15722076/4_ungureanu_maria_mip_act.pdf

Low T is an independent risk factor for metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) development; patients with these clinical conditions should be screened for hypogonadism.

Testosterone replacement therapy (TRT) ameliorates libido, improves bone mass, improves insulin resistance, reduces fat mass and increases lean body mass with no change in body weight.

There are no evidences that testosterone therapy increases the risk of prostate cancer but it is certain that testosterone stimulates growth of metastatic prostate cancer.

TRT has an antiarrhythmic and a vasodilator effect, independent of the nitric oxide effect.

Patients with heart failure have low levels of testosterone, and TRT improves exercise capacity.

Men with low testosterone have risk for premature death.

Cardiovascular adverse effects of testosterone therapy are under discussion.

We need large prospective placebo-controlled randomized trials to determine definitively the cardiovascular risks of TRT.
 
Seftel AD, Kathrins M, Niederberger C. Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis. Mayo Clin Proc. https://www.sciencedirect.com/science/article/pii/S002561961500467X

"Testosterone Therapy in Men With Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline" (Guidelines), published in 2010, serves as an important guide for the treatment of hypogonadal men.

Using the Guidelines as a basis, we searched for the most recent level 1 evidence that continues to support the recommendations or provide an impetus to modify all or some of them.

We performed a systematic analysis with a PubMed query from January 1, 2010, through March 2, 2015, using the following key words: testosterone/deficiency, testosterone/therapeutic use, cardiovascular, morbidity, mortality, screening, sexual function, lower urinary tract symptoms, obstructive sleep apnea, prostate cancer, fertility, bone mineral density, osteoporosis, quality of life, cognitive, erectile dysfunction, and adverse effects.

We identified 17 trials representing level 1 evidence that specifically addressed recommendations made in the Guidelines.

Trials examining outcomes of testosterone replacement therapy in men with severe lower urinary tract symptoms and untreated obstructive sleep apnea were identified, potentially refuting the current dogma against treatment in the setting of these conditions.

Hypogonadal men with type 2 diabetes mellitus and metabolic syndrome were examined in several trials, demonstrating the beneficial effects of therapy on sexual function and insulin sensitivity.

Several trials served as reinforcing evidence for the beneficial effects of testosterone therapy on osteoporosis, muscle strength, and symptoms of frailty.

As in the Guidelines, inconsistent effects on quality of life, well-being, and erectile function were also noted in publications.

Despite controversies surrounding cardiovascular morbidity and treatment in the setting of prostate cancer, no studies examining these issues as primary end points were identified.

The low number of eligible studies since 2010 is a limitation of this analysis.
 
Krakowsky Y, Grober ED. Defining the best candidates for testosterone replacement? Cardiovascular Endocrinology.Publish Ahead of Print. http://journals.lww.com/cardiovascu...e_best_candidates_for_testosterone.99931.aspx

It is widely known that re-establishing physiologic levels of testosterone in symptomatic men with testosterone deficiency (TD) improves the undesirable symptoms associated with low testosterone.

The indications for testosterone replacement therapy (TRT) have been evolving as research continues to find out who are the best candidates for therapy.

Recently, concerns on the association of TRT and cardiovascular disease have received considerable attention. Before this, considerable attention had focused on the potential dangers of TRT and the risk of prostate cancer.

The vast majority of contemporary evidence suggests that men with treated prostate cancer and no evidence of active disease are appropriate candidates for TRT in the context of symptomatic TD.

Further, current evidence does not support denying TRT to symptomatic men with TD based on stable cardiac disease.
 
Irrational Exuberance in Testosterone Prescribing: When Will the Bubble Burst?
[For Full-Text Email mike.scally@asih.net (Include Title)]

Over the first decade of this century, there was a remarkable escalation in testosterone prescription. On the basis of pharmaceutical industry sales data per capita, this featured a 10-fold increase in the United States and 40-fold increase in Canada of testosterone use, now revealing a $2 billion per annum market for testosterone reflecting a 100-fold increase over 3 decades ago.

Such stunning increases (which exclude pharmacy compounding and illicit nonprescription sources) are inexplicable in the absence of any proven new indications or well-controlled interventional trials over this time. Interestingly, although the increased testosterone usage is reflected in data originating from health sector third parties, such as insurance or governmental health scheme databases, those sources substantially underestimate the magnitude of the increase.

This dichotomy points to the fact that most unjustified testosterone prescribing occurs via doctors not subjected to third-party scrutiny such as through formulary and/or reimbursement restrictions in the veterans administration system or in the health systems of a Canadian province and Australia. Although some traditionalists may decry such restrictions as an intrusion on the exclusive patient-doctor relationship, the evidence suggests that third-party involvement provides indispensable independent scrutiny necessary to restrain unjustified prescribing.

This is particularly necessary for prescribing driven by exuberance of industry and/or individual enthusiasts or by misguided patient demand confected by internet-based illusions of rejuvenation whereby testosterone is used as a tonic for sexual dysfunction, fatigue, or simply ageing, so aptly skewered by the inimitable Stephen Colbert (http://www.cc.com/video-clips/idoutl/the-colbert-report-cheating-death---low-t).

The privacy of the doctor-patient relationship, like its counterparts of legal and confessional privilege, is now struggling to retain its isolation in the face of evidence that only exposure to independent scrutiny can balance the structural weakness of a “market” in which consumers (patients) operate handicapped by an asymmetry of knowledge and doctors remain the monopoly gatekeepers of prescription medicines. Neither weakness can realistically be remedied to free the invisible hand of the “market” to operate in its idealized fair fashion.

Handelsman DJ. Irrational Exuberance in Testosterone Prescribing: When Will the Bubble Burst? Med Care. 2015;53(9):743-5. http://journals.lww.com/lww-medical...xuberance_in_Testosterone_Prescribing_.1.aspx
 
Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, et al. Testosterone and “Age-Related Hypogonadism” FDA Concerns. New England Journal of Medicine. 2015;373(8):689-91. http://www.nejm.org/doi/full/10.1056/NEJMp1506632

Testosterone products have been approved by the Food and Drug Administration (FDA) for replacement therapy in men with “classic hypogonadism” — primary or secondary hypogonadism caused by specific, well-recognized medical conditions, such as Klinefelter's syndrome, pituitary injury, or toxic damage to the testicles.1 Treatment with testosterone to restore serum concentrations in men with classic hypogonadism has long been considered the standard of care.

On the basis of this intended use, the FDA has required only that testosterone products reliably bring low serum testosterone concentrations into the normal range, defined as the concentrations seen in healthy young men. The FDA has not mandated that clinical trials show improvements in signs or symptoms of hypogonadism in order for a testosterone product to be approved.

In recent years, however, testosterone use has increased markedly among middle-aged and elderly men for a controversial condition that the FDA calls “age-related hypogonadism.” This condition, also referred to as “late-onset hypogonadism,” is typically diagnosed in men who, for no discernable reason other than older age, have serum testosterone concentrations below the normal range for healthy young men, as well as signs and symptoms that may or may not be caused by low testosterone concentrations.2

Serum testosterone appears to decline as men age,3 and although this decline is usually modest, concentrations can fall below the normal range for healthy young men. In these cases, it is unclear whether coexisting nonspecific signs and symptoms, such as decreases in energy and muscle mass, are a consequence of the age-related decline in endogenous testosterone or whether they are a result of other factors, such as coexisting conditions, concomitant medications, or perhaps aging itself.

In 2002, prompted by the growing numbers of older men using testosterone to delay or treat a variety of signs and symptoms, the Institute of Medicine formed a committee to assess the state of knowledge regarding testosterone therapy. After reviewing the medical literature, the committee concluded that the available evidence on the effects of testosterone therapy in older men was limited and inconclusive.4

To date, there is no definitive evidence that increasing serum testosterone concentrations in these men is beneficial and safe, and the need to replace testosterone in older men who lack a distinct, well-recognized cause of hypogonadism remains debatable.

Despite these uncertainties, older men have been the target of direct-to-consumer advertisements for testosterone products and nonbranded disease-awareness campaigns for “low T” that imply treatment benefits that are not supported by substantial evidence from controlled trials. An analysis by the FDA showed that more than 80% of prescription testosterone users are men between 40 and 74 years of age.

The most common International Classification of Diseases, 9th revision (ICD-9) diagnosis code associated with testosterone use is testicular hypofunction, not elsewhere classified (ICD-9 code 257.2), which does not specify a distinct, well-recognized cause of hypogonadism.1

The average duration of use in these patients is relatively brief (approximately 6 months over the 5-year period examined), which is inconsistent with the need for lifelong hormone replacement in men with classic hypogonadism.

The FDA also sampled a health claims data set and found that 28% of men who received a new testosterone prescription had no evidence of a prior serum testosterone measurement.1 Others have estimated even higher rates of omission of testing.5 Given these patterns of use, it appears that a majority of men prescribed testosterone may have age-related hypogonadism rather than classic hypogonadism.

These findings are troubling in light of evidence from recent large observational studies that suggests potential cardiovascular risk associated with testosterone use. The FDA reviewed five retrospective cohort studies and two meta-analyses of controlled trials on this topic.1

Two of the cohort studies found a significant increase in cardiovascular events associated with testosterone use, whereas two others found a significant reduction in all-cause mortality. The final study found no significant change in the risk of hospitalization for myocardial infarction among testosterone users.

The authors of these five studies evaluated a variety of data sources, patient populations, testosterone formulations, and outcomes over a range of follow-up times and performed different statistical adjustments for confounders or time-varying covariates, making it difficult to integrate the findings in a meaningful manner.

The meta-analyses also had conflicting findings — one reported an increased risk of broadly defined cardiovascular-related adverse events among testosterone users; the other reported no additional risk of major adverse cardiovascular events.

Although the limitations and potential confounders or biases in these studies preclude a clear conclusion regarding the role of testosterone therapy in adverse cardiovascular outcomes, a possible association cannot be overlooked. To date, no randomized, controlled trials have been appropriately designed to evaluate cardiovascular outcomes with testosterone use.

The FDA convened an advisory committee meeting in September 2014 to discuss the use of testosterone for age-related hypogonadism and the recent signal of cardiovascular risk. The committee members concluded that the available evidence supports an indication for testosterone therapy only in men with classic hypogonadism and that drug labels should state that the efficacy and safety of testosterone products have not been established for age-related hypogonadism.

In addition, because there is no evidence of laboratory testing before the initial testosterone prescription for some men, committee members recommended adding a statement to drug labels about the need to confirm low serum testosterone concentrations before initiating treatment. The committee acknowledged the limitations of the available data on adverse cardiovascular events but concluded that the totality of the evidence suggests a weak signal of cardiovascular risk and recommended updating drug labels to reflect this information.

The FDA agreed with the advisory committee's recommendations and subsequently required revisions to the labels of all testosterone products. Committee members also commented that only a controlled clinical trial — not observational studies — will be able to definitively determine the effects of testosterone therapy on cardiovascular outcomes.

Given the widespread use of testosterone for age-related hypogonadism, the lack of substantial evidence to support such use, and the unknown effect of the label changes on prescribing patterns, the cardiovascular safety of testosterone products in older men remains an important public health concern.

To better determine the effects of testosterone therapy on cardiovascular outcomes among users, the FDA is requiring companies that manufacture these products to conduct a controlled clinical trial. We are encouraging companies to work together on a single trial. We believe the health of American men will be well served by the presence of accurate drug labels and reliable data to inform clinical decision making.


REFERENCES

1. FDA briefing document for the joint meeting for Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSARMAC). Silver Spring, MD: FDA Advisory Committee, September 17, 2014 (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM412536.pdf).

2. Wang C, Nieschlag E, Swerdloff R, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Int J Impot Res 2009;21:1-8.

3. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001;86:724-731.

4. Institute of Medicine. Testosterone and aging: clinical research directions. Washington, DC: National Academies Press, 2004.

5. Layton JB, Li D, Meier CR, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab 2014;99:835-842.
 
Dr Scally, do you think that TRT as we know it is in danger? or will big pharma and big money prevail and keep us old guys in TRT long into the future
 
[No] Association Between Testosterone Supplementation Therapy and Thrombotic Events

Ramasamy R, Scovell J, Mederos M, Ren R, Jain L, et al. Association Between Testosterone Supplementation Therapy and Thrombotic Events in Elderly Men. Urology. 2015;86(2):283-6. http://www.goldjournal.net/article/S0090-4295(15)00405-7/abstract

OBJECTIVE: To determine the prevalence of thrombotic events and all-cause mortality in men older than 65 years with hypogonadism treated with testosterone therapy (TST).

PATIENTS AND METHODS: We retrospectively reviewed the charts of 217 hypogonadal men >65 years. We compared men who received TST (n = 153) to hypogonadal men (n = 64) who did not receive TST.

We evaluated all-cause mortality, prevalence of myocardial infarction (MI), transient ischemic attack (TIA), cerebrovascular accident (CVA or "stroke"), and deep vein thrombosis/pulmonary embolism (DVT/PE). All events were verified by contacting patients.

We excluded men with previous thrombotic events, men previously on androgen deprivation therapy, and men who had used TST before age of 65 years.

RESULTS: Median age and Charlson Comorbidity Index of men on TST (74y; 5.1) was similar to hypogonadal men not on TST (73y, P = .48; 5.3, P = .36). Median follow-up was 3.8 vs 3.5 years (TST vs no TST).

No man on TST died, whereas 5 hypogonadal men who did not receive TST died (P = .007).

There were 4 thrombotic events (1 MI, 2 CVA/TIA, and 1 PE) in men who received TST and 1 event (CVA/TIA) among men who did not receive TST (P = .8).

All events (1 death, 6-month follow-up) occurred at least after 2 years of follow-up.

CONCLUSION: There was increased all-cause mortality in hypogonadal men not treated with testosterone compared to men who received TST. There was no difference in prevalence of MI, TIA/CVA, or PE between patients treated with testosterone and hypogonadal men not treated with testosterone.
 
I think notable is the fact that many prescriptions are written with dosages that put levels higher than they ever were naturally in most men. Most men doing 200 mg a week are going for drug like supraphysiological levels and effects that were never intended in their body's normal healthy state
 
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